With Alzheimer’s disease and other forms of dementia affecting millions of elders, the need for safe remedies to both halt the progression and help treat symptoms is greater than ever before. One of the greatest challenges for caregivers and family members of patients with cognitive impairment is handling aggression and other disturbing behavioral issues that accompany memory loss in approximately 90% of dementia patients. One traditional remedy that is used for aggression is Yokukansan, a Kampo remedy, which is the traditional herbal system of Japan.

Yokukansan

Yokukansan was introduced to the Kampo system as early as the Ming dynasty in 1555, by Xue Kai and Xue Ji, as a remedy for restlessness and agitation in children; however, it existed for at least 1000 years prior to this in Traditional Chinese Medicine. Also known as Yi-Gan San (抑肝散) in China, the formula contains powdered herbs: 4 parts Atractylodis lanceae root, 4 parts Poria, 3 parts Cnidium root, 3 parts Uncaria uncis cum ramulus, 3 parts Angelica root, 3 parts Bupleurum root, and 1.5 parts Glycyrrhiza root, all blended and dosed at 2.5 grams TID. The Kampo medical system persists in modern times and is commonly employed by licensed physicians who dispense formulas as concentrated powders. Yokukansan is approved by the Japanese Ministry of Health, covered under the National Health Insurance plan, and was recommended by the Japanese Society of Neurology in 2010 for the management of dementia symptoms.1,2

A Cochrane meta-analysis reported Yokukansan to improve neuropsychiatric symptoms and daily living scores in dementia patients, and without toxicity or significant side effects.5 Several clinical trials examining Alzheimer’s and dementia patients have shown a statistically significant improvement in agitation, aggression, and hallucination, again without adverse events.6-9 One randomized, multicenter, double-blind, placebo-controlled study investigated the effects of Yokukansan on 120 schizophrenic patients from 34 psychiatric hospitals in Japan, who had responded poorly to other anti-psychotic medications.10 While the formula was not superior to placebo in terms of cognitive improvements, statistically significant improvements were seen in hostility and excitability compared to placebo.10 A similar study reported efficacy in reducing behavioral symptoms in schizophrenics.11 Several clinical studies have shown improvement in irritability, agitation, and hyperactivity in children with pervasive developmental disorders.12,13 One clinical trial of 20 patients with Charles Bonnet syndrome (the triad of complex visual hallucination associated with ocular pathology causing visual deterioration, but with preserved cognitive status) reported Yokukansan to significantly reduce visual hallucinations within 2 to 4 weeks.14

Mechanisms of Action

Although the herbal combination would contain hundreds, if not thousands, of “active” constituents, some of Yokukansan’s activity has been credited to 18β-glycyrrhetinic acid in licorice and to geissoschizine methyl ether in Uncaria15,16; both are shown to be well absorbed orally and to be detectible in the plasma within 0.5 to 1 hour following ingestion.17 Animal studies have demonstrated neuroprotective effects,18 serotonin (5-HT) and dopamine agonism,10,19,20 GABAergic effects,22 and glutamate-receptor blockade.23 Yokukansan significantly increases the density of serotonin receptors in the prefrontal cortex,24 and Uncaria and its constituent, geissoschizine methyl ether, has a partial agonistic effect on 5-HT(1A) receptors and is believed to contribute to the anti-aggressive effects of the formula.24,25

Cognitive and memory-enhancing effects have been demonstrated in animals, an effect reversed by the use of muscarinic-receptor antagonists27 [suggesting that Yokukansan may have cholinergic effects]. Yokukansan may protect functional neurons from the degenerative effects of β-amyloid accumulation,28 as does isolated Uncaria.29 Yokukansan significantly increases high-potassium-evoked potentiation of acetylcholine release, and ameliorates spatial memory impairment in a rat model of early-phase Alzheimer’s disease.30 Yokukansan also attenuates morphine tolerance and naloxone-precipitated morphine withdrawal symptoms without diminishing analgesic effects in animal studies, with effects credited to 18β-glycyrrhetinic acid and geissoschizine methyl ether’s ability to reduce expression of α(2A)-adrenoceptor in the brainstem.31

Safety

Although the formula is very well tolerated and meta-analyses have reported few side effects, there are isolated reports of severe hypokalemia, perhaps due to the licorice component.32 Pseudoaldosteronism is a known side effect of high doses of licorice, and although the amount is low in Yokukansan, genetic variations in the 12β-hydroxysteroid enzyme may leave some people susceptible to hypokalemia-related hypertension. To be on the safe side, potassium supplementation and/or routine testing of serum potassium may be prudent when using the formula.33 Numerous clinical trials on patients with dementia-related behavioral disorders have reported significant decreases in hallucinations, agitation, anxiety, irritability, aggression, tension, depressive mood, hostility, suspiciousness, motor retardation, uncooperativeness, and excitability with Yokukansan, without observed or laboratory side effects,32-39 and only 1 study reported 2 cases of hypokalemia.40

Table 1. The 7 Herbs in the Yokukansan Formula

Scientific Name

Chinese Name

Common Names

Medicinal Component Used

Bupleurum

Chai Hu 柴胡

Hare’s ear root, Thorowax root

Roots

Poria cocos

Fu Ling 茯苓

Sclerotium of tuckahoe, China root, hoelen, Indian bread

Woody mushroom / fruiting body

Cnidium officinale or Ligusticum chaunxiong

Japanese Chuan Xiong 川芎 (Cnidium)

Sichuan lovage root (Ligusticum)

Rhizomes

Glycyrrhiza glabra

Gan Cao 甘草

Licorice root

Angelica sinensis

Dong Quai, Dang Gui 當歸

Tang kuei

Roots

Uncaria cum-uncis

Gou Teng 芶藤

Stems of gambir vine, gambir, uncaria vine

Vine bark

Atractylodis

Cang Zhu 蒼术

Rhizomes

Jillian Stansbury, ND, has practiced in SW Washington for nearly 20 years, specializing in women’s health, mental health, and chronic disease. She holds undergraduate degrees in medical illustration and medical assisting, and graduated with honors in both programs. Dr Stansbury also chaired the botanical medicine program at NCNM and has taught the core botanical curricula for more than 20 years. In addition, Dr Stansbury writes and serves as a medical editor for numerous professional journals and lay publicans, plus teaches natural products chemistry and herbal medicine around the country. At present, she is working to set up a humanitarian service organization in Peru and studying South American ethnobotany. She is the mother of 2 adult children, and her hobbies include art, music, gardening, camping, international travel, and the study of quantum and metaphysics.

References

Okamoto H, Iyo M, Ueda K, et al. Yokukan-san: a review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions. Neuropsychiatr Dis Treat. 2014;10:1727-1742.

This web site provides information for professionals and business persons involved in the health food and dietary supplement industry. None of the information in this web site is intended for or should be used as medical advice. Please consult a trained health care practitioner for any medical problems or health conditions.